In the adult mammalian hippocampus, production of new neurons and their integration into the neuronal network is influenced by synaptic activity. Novel roles for the neuropeptide VGF in enhancing neurogenesis in the hippocampus and as an antidepressant-like agent in behavioral models have been demonstrated. The effect of the growth factor brain-derived neurotrophic factor (BDNF) in synaptic plasticity has been well recognized and more recently the promotion of neurogenesis in neural progenitor cells by BDNF has been demonstrated. VGF also enhances synaptic activity and learning and appears to require BDNF signaling for its effects on synaptic activity. Therefore, while the effects of VGF and BDNF on synaptic activity and neurogenesis have been elucidated, a connection between all of these components has not been made. Whether VGF requires BDNF signaling and synaptic activity for its effects on neurogenesis is not known. We hypothesize that the neuropeptide VGF regulates the BDNF pathway and downstream synaptic activity to stimulate adult hippocampal neurogenesis required for VGF's antidepressant-like actions. The first aim of this proposal will test the hypothesis that VGF stimulated neurogenesis requires synaptic activity. The specific stage of neurogenesis which VGF acts upon will be determined and whether VGF also plays a role in survival of newborn cells will be explored. Then the role of activity in VGF-induced neurogenesis will be studied. This will be accomplished by stimulating proliferation of neural progenitor cells with VGF and then blocking synaptic activity with pharmacological antagonists to see if activity is necessary for VGF-induced neurogenesis. The second aim will test the hypothesis that VGF-induced neurogenesis is required for the antidepressant-like effects of VGF. The proliferating population of hippocampus will be ablated using x-ray irradiation and then the effect of VGF on behavior in the irradiated mice will be assayed. The third aim will study if the effect of VGF on neurogenesis is mediated by BDNF signaling. BDNF receptor activation will be blocked in vitro using molecular approaches and in vivo using genetically modified mice to determine if VGF requires BDNF signaling for neurogenesis. The mechanism of how VGF and BDNF interact to regulate neurogenesis will be studied using biochemical and molecular manipulations. Specifically, whether VGF directly binds or activates the BDNF receptor will be studied. Importantly, the influence of secreted neuropeptides such as VGF on neurotrophin function is not known. These interactions would allow the nervous system network to exert a finer level of control over processes including neurogenesis which greatly impact brain function. Understanding how neuropeptides influence neurogenesis will reveal mechanisms underlying disorders in which neurogenesis and/or activity have been implicated such as depression, epilepsy, stroke and neurodegenerative disease. In addition, the neuropeptide VGF may represent a way to regulate proliferation of stem cells which has therapeutic potential. PUBLIC HEALTH RELEVANCE: The birth of new neurons in the adult brain especially in the hippocampus, termed adult neurogenesis, is thought to play a role in the pathogenesis and treatment of a number of disorders including depression, epilepsy, stroke and neurodegenerative diseases. Understanding how neuropeptides such as VGF and growth factors such as neurotrophins work in concert to enhance neurogenesis and affect behavior will thus lend insight into the mechanisms underlying neurological disease and provide new drug targets. In addition, the neuropeptide VGF may represent a way to regulate proliferation of stem cells which has therapeutic potential.